title: EGFR-mediated Akt and MAPKs signal pathways play a crucial role in patulin-induced cell proliferation in primary murine keratinocytes via modulation of Cyclin D1 and COX-2 expression.
abstract: Patulin (PAT), a present day major contaminant of commercial apple and apple products is reported to be carcinogenic, embryotoxic, and immunotoxic. While oral and inhalation are considered to be the most prevalent routes of exposure to this toxin, exposure through skin is now being extensively investigated. Our previous study showed that short-term dermal exposure to PAT resulted in toxicological injury to the skin, while long-term exposure induced skin tumorigenesis. In this study, we explore the mechanism involve in proliferation of mouse keratinocytes by PAT. Our study revealed that PAT rapidly induces phosphorylation of EGFR, activation of the Ras/MAPKs, and Akt pathways. This in-turn leads to the activation of NF-κB/AP-1 transcription factors which then binds to the promoter region of the cell growth regulatory genes Cyclin D1 and COX-2 inducing their expression leading ultimately to PMKs proliferation. Inhibition of EGFR or the Ras/MAPKs, PI3/Akt pathways with different pharmacological inhibitors or knockdown of NF-κB, c-jun, c-fos, Cyclin D1, and COX-2 with siRNA inhibited PAT-induced PMKs proliferation.
authors.affiliation: Food, Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India.
authors.forename: Shamshad
authors.initials: S
authors.lastname: Alam
authors.forename: Anu
authors.initials: A
authors.lastname: Pal
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.forename: Premendra D
authors.initials: PD
authors.lastname: Dwivedi
authors.forename: Mukul
authors.initials: M
authors.lastname: Das
authors.forename: Kausar M
authors.initials: KM
authors.lastname: Ansari
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D010365:Patulin / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D010365:Patulin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: mycotoxin; patulin; primary mouse keratinocytes; proliferation; signaling pathways